Cancer

Cell BiologyBIO 3450Fall 2015

Chapter 24 Cancer

What is cancer?Cancer is a term used for

diseases in which abnormal cells divide without control and are able to invade other tissues.

htwww.cancer.gov/cancertopics

Fig. 24.2

Grow too fast

Do not die

Independence from environment

Access to nutrient supply(Angiogenesis)

Migrate (Metastasis)

Fig. 24.1

Grow too fast

Do not die

Independence from environment

Access to nutrient supply(Angiogenesis)

Migrate (Metastasis)

Fig. 24.3

https://www.youtube.com/watch?v=jjfYQMW_nek

https://www.youtube.com/watch?v=8VSgOeJy4dQ

https://www.youtube.com/watch?v=bdWRZd19swg

https://www.youtube.com/watch?v=Ep_nCSEDeAE

http://www.ncbi.nlm.nih.gov/pubmed/?term=massague+j+review

Figure 24.8 The development and metastasis of human colorectal cancer….

Very early steps:

Abnormal vs normal proliferation of cells in colonic crypt

Figure 24.8 The development and metastasis of human colorectal cancer….

Aberrant coloniccrypt foci(Multiplicity = 2)

Adenoma

Adenocarcinoma

Figure 24.8 The development and metastasis of human colorectal cancer and its genetic basis.

Figure 16.30 Wnt signaling pathway.

Induces expression of myc and other proliferation genes

Figure 16.30 Wnt signaling pathway.

Induces expression of myc and other proliferation genes

Experimental Figure 24.7

Figure 24.8 The development and metastasis of human colorectal cancer and its genetic basis.

Remember ras in cell signaling??

Figure 16.20 Ras/MAP kinase pathway.

Experimental Figure 24.7

Figure 24.8 The development and metastasis of human colorectal cancer and its genetic basis.

Remember p53 in cell signaling??

• p53 is a transcription factor

• In normal cells, p53 is at low concentration AND has a short lifetime; When DNA damage is present in cells, p53 is stabilized.

• p53 activates expression of genes involved in DNA repair/replication AND genes to arrest cells in G1 and G2.

• If damage is bad enough, p53 turns on genes to induce programmed cell death (apoptosis).

Key gene turned on by p53 in cell cycle inhibition: p21CIP1

The Genome Gatekeeper: p53- Cell cycle arrest with damaged DNA

How is p53 Regulated?

•p53 is mutated in 50% of all tumors

Destabilizes in normal cells

DNA damage stabilizes p53 by phosphorylation

MDM2: when bound to p53, leads to p53 degradation by catalyzing the addition of Ub

ATM/ATR : phosphorylate p53, displace MDM2, stabilize p53.

Figure 24.8 The development and metastasis of human colorectal cancer and its genetic basis.

Figure 24.26 G1 arrest in response to DNA damage.

The participation of multiple mutations (it has been estimated that development of cancer occurs after accumulation of 6-8 mutations)—also means that:

a) There is a lot of genetic diversity (i.e., cancer tissue is comprised of polyclonal cells)

b) There are complex readjustments of cell biochemistry—i.e., changes in expression of more than the genes that are mutated (Fig. 24.10, below).

c) Prognosis depends on the specifics of the cancer and individual.

Other “hot topics” in cancer research today:

a) The roles of microRNA’s (probably serve as mediators of multiple phenotypic changes in the cells, and probably their interaction with other cells, especially of the immune system);

Tumor releases miRNA Affects

macrophagesMacrophages do not kill the tumor, and sometimes release factors that

assist the tumorb) Other contributions from

macrophages…

Other “hot topics” in cancer research today:

a) The roles of microRNA’s (probably serve as mediators of multiple phenotypic changes in the cells, and probably their interaction with other cells, especially of the immune system);

Tumor releases miRNA Affects

macrophagesMacrophages do not kill the tumor, and sometimes release factors that

assist the tumorb) The roles of cancer stem cells (i.e.,

tumors have a small number of abnormal stem cells that differ from most of the other cells of the tumor and thus might be resistant to the therapeutic treatment that kills most of the tumor, and thus the cancer returns after treatment.

Other “hot topics” in cancer research today:c) EMT (epithelial-mesenchymal

transition) and MET (mesenchymal-epithelial transition).

Many of the cells in the body undergo transitions from proliferative, migrating cells (“mesenchymal phenotype) to a non-proliferating, adherent (non-migrating) stage (“epithelial” phenotype) as part of their natural differentiation (as happens in the GI tract in the example noted here:

Some tumor cells also undergo EM (EMT) and ME (MET) that affects their behavior, including tendency to metastasize, susceptibility to chemotherapy, etc.

Another interesting (and important) concept: Acquisition of multiple mutations takes time, so:

a) Risk of most cancers increases with age.

b) One can be watchful for some cancers based on any increased risk factors (family history, exposures, etc.)

c) Minimize controllable risk factorsd) Detect (and treat) early

Fig. 24.6

What are the major kinds of cancer?

2008 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2008.

Men294,120

Women271,530

•26% Lung & bronchus

•15% Breast

•9% Colon & rectum

• 6% Pancreas

• 6% Ovary

• 3% Non-Hodgkin lymphoma

• 3% Leukemia

•3% Uterine corpus

• 2% Liver & intrahepaticbile duct

• 2% Brain/ONS

•25% All other sites

Lung & bronchus 31%

Prostate 10%

Colon & rectum 8%

Pancreas 6%

Liver & intrahepatic 4%bile duct

Leukemia 4%

Esophagus 4%

Urinary bladder 3%

Non-Hodgkin 3% lymphoma

Kidney & renal pelvis 3%

All other sites 24%

Tobacco Use in the US, 1900-2004

*Age-adjusted to 2000 US standard population. Source: Death rates: US Mortality Data, 1960-2004, US Mortality Volumes, 1930-1959, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006. Cigarette consumption: US Department of Agriculture, 1900-2004.

Per capita cigarette consumption

Male lung cancer death rate

Female lung cancer death rate

More than 3,000 chemicals are present in tobacco smoke, including at least 60 known carcinogens such as nitrosamines and polycyclic aromatic hydrocarbons.

Hydrophobic(stored in fat)

How does the body get rid of this stuff?

Primarily by cytochrome P450-mediated oxidations

plus subsequent conjugation

More hydrophilic(eliminated in bile/

sometimes conjugated)

Fig. 24.28

Additional sources of genetic mutation:1) Inherited--you already have it2) Spontaneous errors in gene sequence

chemical instability (which is usually repaired)mistakes in DNA synthesis or repairgenetic recombination/translocation

Note wrong structure

Additional sources of genetic mutation:1) Inherited--you already have it2) Spontaneous errors in gene sequence

chemical instability (which is usually repaired)mistakes in DNA synthesis or repairgenetic recombination/translocation

Figure 24.20 Bcr-Abl protein kinase.

Figure 24.22 Chromosomal translocation in Burkitt’s lymphoma.

Additional sources of genetic mutation:3) Other kinds of chemical modification or damage

a) Radiation

b) Reactive oxygen species (ROS):

H2O2, OH., O2.

(hydrogen peroxide, hydroxyl radical, superoxide)produced by defects in cellular redox pathways and inflammation

Additional sources of genetic mutation:3) Other kinds of chemical modification or damage

c) Other carcinogens (as pro-carcinogens)

And sometimes direct carcinogens (such as nitrogen mustard and other alkylating agents).

4) DNA repair defects (Lodish Table 24-2: you do not need to know the items in this table)

Fig. 24.29

What are some of the differences in inherited gene defects vs those acquired after birth (somatic)?

Oncogenes not hereditary (why?)

Tumor suppressor mutations can be inherited, followed by somatic (or gotten by two somatic mutations)

Fig. 24-13 Retinoblastoma

Two mechanisms for loss of heterozygosity (LOH) of tumor-suppressor genes.

Fig. 24-14

What types of models are used to study cancer?

Cells in culture (Fig. 24.4 and 24.5, on right):

Animal models with tumor xenografts (surgical implantation of cancer cells in immunosuppressed mice)

Animal models that develop cancer:Genetic pre-disposition (natural and genetically engineered) e.g., “Min” mouse with APC mutationChemically induced tumors

Human w/cancerAnalysis of tumor tissueEpidemiologic studies

What types of mutations cause cells to behave in these abnormal ways?

Most cancer mutations are in cell signaling pathways

Some examples you should already know about are highlighted w/boxes here.

This is not in your textbook, its from the last edition, Fig. 25-15

Figure 24.11 Seven types of genes/proteins that participate in controlling cell growth and proliferation.

Examples of oncogenic mutations:Mutation of a growth regulatory receptor to be “on” always

Mutated receptor Mutated signaling (e.g. ras)

Mutated ras or ras activator/terminator

Fig. 24-17

Example of a tumor suppressor mutation: Mutation of a cell cycle regulatory protein (Rb, retinoblastoma protein)

Fig. 24-24

A reminder about the TGF pathway, with illustration of multiple steps relevant to cancer

Fig. 24-23

Progression Through Cell Cycle is Controlled at Several Key Checkpoints

http://nobelprize.org/medicine/educational/2001/index.html

More on ATM, p53, etc.

Fig. 24-26

Figure 24.30 Loss of telomeres normally limits the number of rounds of cell division.

Most cancer mutations are in cell signaling pathways..and it

goes on and

on and on…

Fig. 25-15

& TGF pathwayas well as others involved in development

Fig. 25-15

& TGF pathwayas well as others involved in development

See why you

learned all this

stuff?